tbuckley/cabot-search huggingface dataset:
Capecitabine Maintenance in Metastatic Nasopharyngeal Carcinoma
Authors: Shuvadeep Ganguly, Ajay Gogia
Journal: JAMA Oncology (2022)

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Immunogenicity and Safety of Beta-Adjuvanted Recombinant Booster Vaccine
Authors: Odile Launay, Marine Cachanado, Liem B Luong Nguyen, Laetitia Ninove, Marie Lachâtre, Inès Ben Ghezala, Marc Bardou, Catherine Schmidt-Mutter, Karine Lacombe, Fabrice Laine, Jean-Sébastien Allain, Elisabeth Botelho-Nevers, Marie-Pierre Tavolacci, Christian Chidiac, Patricia Pavese, Bertrand Dussol, Stéphane Priet, Dominique Deplanque, Amel Touati, Laureen Curci, Eleine Konate, Nadine Ben Hamouda, Anissa Besbes, Eunice Nubret, Florence Capelle, Laurence Berard, Alexandra Rousseau, Eric Tartour, Tabassome Simon, Xavier de Lamballerie
Journal: New England Journal of Medicine (2022)
Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
Authors: Jennifer A. Frontera, Naomi M. Simon
Journal: JAMA Psychiatry (2022)

<h3>Importance</h3> Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC. <h3>Observations</h3> Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors. <h3>Conclusions and Relevance</h3> Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.
Erythematous Plaque on the Lower Extremity of an Older Adult Man
Authors: Dídac Marín-Piñero, Monica Quintana-Codina, María Teresa Fernández-Figueras
Journal: JAMA Dermatology (2022)

A man in his early 70s presented with a 2-year history of a mildly pruritic, erythematous, gradually enlarging lesion on his left calf with no identifiable cause. What is your diagnosis?
Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer
Authors: Adam J. Schoenfeld, Hira A. Rizvi, Danish Memon, Narek Shaverdian, Matthew J. Bott, Jennifer L. Sauter, C. Jillian Tsai, Jayon Lihm, David Hoyos, Andrew J. Plodkowski, Rocio Perez-Johnston, Peter Sawan, Jacklynn V. Egger, Benjamin D. Greenbaum, Andreas Rimner, Gregory J. Riely, Charles M. Rudin, Valerie W. Rusch, Daniel R. Gomez, Matthew D. Hellmann
Journal: Clinical Cancer Research (2022)

Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions.Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy.OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.
Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression
Authors: Li-Peng Hu, Wuqing Huang, Xu Wang, Chunjie Xu, Wei-Ting Qin, Dongxue Li, Guangang Tian, Qing Li, Yaoqi Zhou, Suyuan Chen, Hui-Zhen Nie, Yujun Hao, Jian Song, Xue-Li Zhang, Jan Sundquist, Kristina Sundquist, Jun Li, Shu-Heng Jiang, Zhi-Gang Zhang, Jianguang Ji
Journal: Molecular Therapy (2022)

Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Sweden identified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio = 0.50) and metastasis (hazard ratio = 0.44) compared with patients without terbinafine administration. In multiple mouse models of CRC, administration of terbinafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation, and cell-cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltration, and restoring antitumor immune response.
Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs
Authors: Ho-Sup Lee, Hao Sun, Frédéric Lagarrigue, Sarah Hyun Ji Kim, Jay W. Fox, Nicholas E. Sherman, Alexandre R. Gingras, Mark H. Ginsberg
Journal: The Journal of Experimental Medicine (2022)

Rap1 GTPase drives assembly of the Mig-10/RIAM/Lamellipodin (MRL protein)–integrin–talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag–based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (Ptsn), a regulatory subunit of protein phosphatase 1, is a component of the complex. Ptsn mediates dephosphorylation of Rap1, thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes Ptsn, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18−/− mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable, in part, to defective activation of integrins αLβ2 and α4β7. Ppp1r18−/− T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, Ptsn enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of Ptsn ameliorates T cell–mediated colitis.
Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors
Authors: Daniel V Kalinovsky, Alexey V Kibardin, Irina V Kholodenko, Elena V Svirshchevskaya, Igor I Doronin, Mariya V Konovalova, Maria V Grechikhina, Fedor N Rozov, Sergey S Larin, Sergey M Deyev, Roman V Kholodenko
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Both ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer. Methods Anti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models. Results The ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model. Conclusion These findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.
P1553: PREVALENCE AND IMPACT OF IRON DEFICIENCY ANEMIA IN A COHORT OF PATIENTS WITH CROHN’S DISEASE
Authors: A. Abomhya, W. Tai, W. Saadedeen, O. Ajala, Z. Abdulsada, A. Sadeghi, J. Shim, R. Mohamed
Journal: HemaSphere (2022)

Background: Iron deficiency anemia (IDA) is the most common cause of anemia worldwide. Crohn’s disease (CD) is a chronic inflammatory disease that affects the digestive system and is associated with a significant risk of chronic blood loss. USA has one of the highest prevalences of CD worldwide, with 214 per 100,000 diagnosed with CD. The nature of CD puts the patients at risk of IDA as well as anemia of chronic disease. Few studies evaluated the association between IDA and CD. Aims: We aimed to estimate the prevalence of IDA in patients with CD. Secondary outcomes included the effect of IDA on mortality, the length of stay, all-cause 30-day non-elective readmission rate, and total cost of hospitalization. Methods: We queried the Nationwide Readmission Database 2018 using ICD-10-CM codes to identify all adult patients admitted with a diagnosis of CD. Patients with a comorbid diagnosis of IDA were identified. The case selection process is summarized in Figure 1. Median and IQR were used to describe Continuous variables, and proportions were used with categorical variables. Comparison between groups was performed by Mann Whitney test for continuous variables and Chi-Square test for Categorical variables. Multivariate regression analysis was performed to study the impact of IDA on inpatient mortality and non-elective readmissions. Statistical analyses were performed using SPSS Version 25 (IBM Corporation, Armonk, NY, USA). Results: We extracted 72,076 index hospitalization records for CD, 8.1% had IDA. CD patients with IDA had increased length of stays in days (4; Interquartile Range (IQR): 2-6 vs. 3; IQR: 2-5, P <0.001), increased median total charges ($35,160; IQR: $19,786 - $64,126 vs. $31,299; IQR: $17,226 - $59,561, P <0.001) and were more common to require blood transfusion during hospitalization (13.6% vs. 3.4%, P <0.001) compared to CD patients without IDA, respectively. There was no statistically significant difference in mortality between CD patients with and without IDA (Odds ratio (OR): 0.79; 95% confidence interval (CI): 0.595-1.049, P= 0.103). IDA was independently associated with increased odds of all-cause 30-day non-elective readmission (OR: 1.254; 95% CI: 1.154-1.363, P <0.001). Image:Summary/Conclusion: IDA is a common extraintestinal manifestation of Crohn’s disease. We observed a significant association between IDA and worse hospitalization outcomes in our nationwide cohort. Early recognition and management of IDA among patients with CD might be important to improve hospitalization outcomes. Further research studies are needed to improve screening, diagnosis, and management of IDA in this patient population.
P749: PROGNOSTIC SIGNIFICANCE OF SERIAL CIRCULATING TUMOR DNA STATUS POST TREATMENT IN MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA
Authors: H. Tong, X. Zhou, W. Lang, C. Mei, Y. Ren, L. Ma, G. Xu, L. Xu, Y. Li
Journal: HemaSphere (2022)

Background: A major advance in our understanding of Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) biology has been the implementation of next generation sequencing (NGS) which influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. Circulating tumor DNA (ctDNA) sequencing, as as a novel and minimally invasive measure, was reported to exhibit excellent correlations with matched bone marrow NGS in MDS and AML. However, the clinical relevance of dynamic ctDNA monitor during active treatment is unknown. Aims: In this study, we assessed the role of ctDNA as a biomarker to monitor therapeutic response and clonal evolution in MDS and AML. Methods: Thirty-one MDS and AML patients who had both bone marrow NGS and ctDNA at baseline were included for concordance analysis. Twenty-seven patients who had at least two serial ctDNA assessment with at least one month interval were included for dynamic ctDNA analysis. Targeted deep sequencing was performed on bone marrow and ctDNA using a customized panel of 165 genes known to be recurrently mutated in MDS and acute myeloid leukemia. Results: Thirty out thirty-one patients were identified with ctDNA mutation at baseline. Diagnostic ctDNA and matched bone marrow DNA exhibited excellent correlations with variant allele frequencies (VAFs) (R2=0.721, p<0.001). For 27 patients who had ctDNA mutation in baseline and treated with HMA or chemotherapy, the average mutation VAFs at the end of treatment was lower in patients achieving a CR/CRi versus those with mCR, mLFS or SD (2.7% vs 24.1%, respectively, p<0.001). As expected, mutation VAFs from all patients with treatment failure did not decrease during treatment. (Figure 1). Similarly, the average decrease in mutation VAFs from pretreatment to end of treatment was greater in patients achieving a CR versus those who did not (87.7% vs 35.5%, respectively, p= 0.001). ctDNA negative post treatment was associated with longer PFS (median PFS not reached (NR) vs. 5.6 (95% CI 4.08-7.13) months; P=0.009)(Fig 2A) and OS (median OS NR vs. 12.0 (95% CI 9.08-15.0) months; P=0.023) (Fig 2B). Seven of ten MDS patients who transformed to AML were identified with lately acquired subclones harboring FLT3 or NF1, mutations involving in signaling pathway. Moreover, new subclones were detected 0.5 to 4 months prior to AML transformation in 4 cases, indicating that genetic progression can predate morphological progression. Image:Summary/Conclusion: ctDNA status post treatment was relevant to clinical response and was of prognostic significance for disease progress and relapse. Dynamic ctDNA changes revealed complex patterns of clonal structure of MDS and AML in response to treatment. ctDNA sequencing could be an attractive, prospective measure for disease monitoring.
Association Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US
Authors: Theresa Ermer, Maureen E. Canavan, Richard C. Maduka, Andrew X. Li, Michelle C. Salazar, Michael F. Kaminski, Matthew D. Pichert, Peter L. Zhan, Vincent Mase, Harriet Kluger, Daniel J. Boffa
Journal: JAMA Network Open (2022)

Clinical trials and compassionate use agreements provide selected patients with access to potentially life-saving treatments before approval by the Food and Drug Administration (FDA). Approval from the FDA decreases a number of access barriers; however, it is unknown whether FDA approval is associated with increases in the equitable use of novel therapies and reductions in disparities in use among patients with cancer in the US.
P1664: IMPACT OF A PROTOCOL USING RITUXIMAB FOR PREVENTION OF RELAPSE IN PATIENTS WITH ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA (ATTP)
Authors: E. Marín Sánchez, E. Fernandes, J. López Marín, F. Tarín, L. Hernandez Mateo
Journal: HemaSphere (2022)

Background: aTTP is a life threatening disease mediated by auto-antibodies directed against ADAMTS13, with reduced activity and high expression of von Willebrand factor large multimers, microthrombi and thrombopenia. Since ADAMTS13 activity is used as a marker for aTTP, it can be used to monitor the emergence of relapses. Aims: To establish a follow-up protocol to anticipate and prevent clinical relapsing disease. Methods: Since February 2015, a protocol has been developed consisting of regular monitoring of ADAMTS13 activity every six months. Rituximab was started when activity was less than 10%, without waiting for the clinical relapse. 24 patients were enrolled, 2 were excluded because of congenital TTP and 2 died in the first 24 h. A total of 20 patients with aTTP have been followed up by the HGUA Hematology Service. The number of relapses before and after the application of the protocol was analized, calculating the annual rate of relapses for each of the follow-up periods. A statistical hypothesis testing was carried out (Wilcoxon). Results: Patients had a mean age of 49.55 ± 14.15, 30% (6) male and 70% (14) female. Cumulative period pre-protocol (years, mean): 5.90 ± 7.89 and cumulative period post-protocol (years, mean): 5.65 ± 1.98. Pre-protocol relapse rate: 0.26 ± 0.46 and post-protocol relapse rate: 0.02 ± 0.08. Clinical relapses prevented (treated with rituximab): 9. Hypothesis contrast (Wilcoxon): p value 0.007 Image:Summary/Conclusion: The use of a protocol for ADAMTS13 monitorization, and the administration of preventive rituximab reduce the number of clinical relapses in patients with acquired TTP under follow-up.
P1514: MULTI-PARAMETRIC CARDIAC MAGNETIC RESONANCE FOR RISK PREDICTION OF HEART FAILURE DEATH IN THALASSEMIA MAJOR
Authors: A. Meloni, L. Pistoia, E. Facchini, S. Armari, G. Roccamo, R. Renni, R. Mattei, A. Vitucci, S. Renne, A. Vallone, V. Positano, F. Cademartiri
Journal: HemaSphere (2022)

Background: Iron-induced heart failure (HF) is the main cause of mortality in patients with thalassemia major (TM). Cardiovascular Magnetic Resonance (CMR) plays a key role in the management of these patients, assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. Aims: We evaluated the prognostic value of CMR parameters in predicting death for HF. Methods: We followed prospectively 1681 white TM patients who performed a baseline CMR exam within the Myocardial Iron Overload in Thalassemia (MIOT) network. All prognostic variables associated with the outcome at the univariate Cox model were placed in the multivariate model and were ruled out if they did not significantly improve the adjustment. Results: At baseline the mean age was 31.11±9.01 years and 874 (52.0%) patients were females. During a mean follow-up of 4.76±2.07 years, 47.3% of the patients changed at least once the chelation regimen, that is switched to a different type of chelator or underwent dose/frequency modification. Sixteen (1.0%) patients died for heart failure. No association was detected between age or gender and HF mortality. Patients who died for HF had significantly lower baseline global heart T2* values (19.45±15.11 ms vs 29.52±12.02 ms, P=0.006) and significantly higher baseline MR liver iron concentration (LIC) values (19.17±15.95 mg/g dw vs 8.72±10.63 mg/g dw, P=0.005) than patients still alive or died for a different cause, but the presence of a pathologic MRI LIC (>3 mg/g dw) was not associated with an increased risk of HF mortality. Heart iron, ventricular dysfunction, and ventricular dilatation were significant univariate prognosticators. In the multivariate analysis the independent predictive factors were a global heart T2*<10 ms (compared to a global heart T2*≥20 ms) (hazard ratio-HR=5.38, 95%CI=1.79-16.22, P=0.003) and ventricular dilatation (HR=4.59, 95%CI=1.55-13.59, P=0.006). The Figure shows the Kaplan–Meier survival curves. The log-rank test revealed a significant difference in the curves for each predictor (severe MIO: P<0.0001 and ventricular dilatation: P<0.0001). Image:Summary/Conclusion: We detected few HF deaths thanks to a MR-guided patient-specific adjustment of the chelation therapy. Severe MIO and ventricular dilatation identified TM patients at high risk for heart failure death. So, a widespread program using CMR exploiting its multi-parametric potential can have considerable power for further opening the prognosis of TM patients.